The giant protein Titin is a master regulator of lymphocyte trafficking

Processing of environmental cues and resilience to mechanical stress are the most fundamental features of circulating leukocytes. Molecular basis of concurrent control of these features are unknown. We show that Titin (TTN), the largest protein encoded by the human genome, is a main controller of T-lymphocyte trafficking. Proteomics and transcriptomics analyses unveil that human T- and B-lymphocytes express five novel TTN isoforms, exhibiting specific localizations to plasma membrane microdomains and different distributions to sub-cellular compartments. Gene silencing shows that the LTTN1 isoform preserves plasma-membrane microvilli, thus regulating selectin-mediated adhesive interactions. LTTN1 also controls integrin activation by chemokines. In contrast, LTTN1 opposes chemotaxis. Signaling analysis shows that LTTN1 mediates rho and rap small GTPases activation by chemokines, but not actin polymerization. Finally, LTTN1 shields cell body and nucleus from the destruction induced by mechanical stress. Therefore, by regulating every step of cell trafficking, LTTN1 emerges as a central controller of T-lymphocyte physiology.